Glaucoma is an ophthalmic disease that leads to irreversible visual impairment. It is the fourth most common cause of blindness and the second most common cause of visual loss in the United States, and the most common cause of irreversible visual loss among African-Americans. Generally speaking, the disease is characterized by a progressive neuropathy caused at least in part by deleterious effects resulting from increased intraocular pressure on the optic nerve. In normal individuals, intraocular pressures range from 12 to 20 mm Hg, averaging approximately 16 mm Hg. However, in individuals suffering from glaucoma, intraocular pressures generally rise above 25 to 30 mm Hg and can sometimes reach 70 mm Hg. Importantly, the loss of vision can result from intraocular pressures only slightly above or even within the statistically normal range, in eyes which are unusually pressure-sensitive, over a period of years. Moreover, extremely high pressures (e.g., 70 mm Hg) can cause blindness within only a few days.
Typical treatments for glaucoma comprise a variety of pharmaceutical approaches for reducing intraocular pressure (IOP) to normal levels. Beta blockers and carbonic anhydrase inhibitors only reduce aqueous humor production, which is needed to nourish the avascular lens and corneal endothelial cells, and the prostaglandins effect is on the uvealscleral outflow pathway which only accounts for 10% of the total facility. There are currently no commercially approved therapeutic agents which act directly upon the trabecular meshwork, the site of increased resistance to aqueous humor outflow and thus responsible for elevated IOP. Therefore, a medical need remains for improved IOP-lowering medications that target this structure. Pharmacological agents which target the trabecular meshwork can provide relief to the significant numbers of patients that do not respond adequately to current IOP-lowering medications and/or cannot tolerate the side effects associated with these agents. There exists a need for effective and cost-practical cytoskeletal active compounds to treat glaucoma, to modulate wound healing after trabeculectomy, and to treat other diseases or disorders that are affected by the integrity of the actin cytoskeleton.
U.S. Pat. Nos. 6,586,425, 6,110,912 and 5,798,380 disclose a method for the treatment of glaucoma using compounds that affect the actin filament integrity of the eye to enhance aqueous humor outflow. These patents also specifically disclose kinase inhibitors and several natural products (latrunculin A, latrunculin B, swinholide A and jasplakinolide), which cause a perturbation of the actin cytoskeleton in the trabecular meshwork or the modulation of its interactions with the underlying membrane. Perturbation of the cytoskeleton and the associated adhesions reduces the resistance of the trabecular meshwork to fluid flow and thereby reduces intraocular pressure.
Natural latrunculins, cytoskeletal active macrolides harvested and isolated from marine sponges such as Latrunculia magnifica, Negombata magnifica, and Spongia mycofijiensis, and from nudibranches, for example Chromodoris lochi, are difficult to obtain in large quantities. Natural Latrunculin analogs and derivatives currently can only be prepared using lengthy, low-yielding, and impractical syntheses (A. B. Smith III et al., J. Am. Chem. Soc. 1992, 114, 2995-3007; J. D. White and M. Kawasaki, J. Org. Chem. 1992, 57, 5292-5300; A. Fürstner et al., Angew. Chem. Int. Ed. 2003, 42, 5358-5360). In addition, often times the synthesis of key intermediates, such as 3,4-disubstituted-thiazolidin-2-ones, do not adequately address (1) the use of potentially lethal reagents, (2) the level of racemization of the final intermediate, and (3) the poor yields of each independent step as well as the overall process (see the above references as well as M. E. F. Braibante, et al. Synthesis, 1999, No. 6, 943-946; J. D. Park, et al., J. Med. Chem. 2002, 45, 911-918; A. Furstner, PNAS, 2005, vol. 102, No. 23, 8103-8108).
There exists a need for simple and practical synthetic procedures to prepare intermediates for the manufacture of novel cytoskeletal active compounds such as latrunculins and/or their analogs.